Cell cultures prepared from fetal mammalian central nerves system were used to study the regulation of neuronal development. Mechanisms which relate to the role of electrical activity during development were investigated. Addition of 0.1 nM vasoactive intestinal peptide (VIP) to dissociated spinal cord cultures resulted in an increase in neuronal survival during electrical blockade. VIP antiserum and receptor blockade with VIP10-28 decreased neuronal survival to a similar extent as treatment with tetrodotoxin. Vasoactive intestinal peptide was shown to act indirectly through non-neuronal background cells to increase neuronal survival during electrical blockade. Conditioned medium obtained from VIP stimulated non-neuronal cultures produced an increase in neuronal survival as compared to that obtained from sister cultures not treated with VIP. Receptor binding studies indicated that VIP sites were present on non-neuronal cultures. Increase in cAMP levels were observed in background cultures treated with 10 nM VIp. We have investigated the possibility that peptide neurotransmitters and neurohormones play a role in the development of their target organ. Early exposure to the neuropeptides was found to permanently affect the expression of neuropeptide receptors, and that this alteration in receptors was of physiological and behavioral importance to the mature animal. For opioid peptides, the developmental effects in rats parallel findings in children exposed in utero to opiate drugs, suggesting that a similar mechanism my operate in humans.